Azacyclooctane and heptane derivatives, their preparation and use in therapy

ABSTRACT

The present invention discloses compounds of formula (1) or (2), any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof; wherein n is 0, or 1; R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalky-alkyl, aryl or aralkyl; and R 1  is aryl which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cyloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF 3 , OCF 3 , CN, amino, nitro, aryl and a monocyclic 5 to 6-membered heteroaryl group a monocyclic 5 to 6-membered heteroaryl group which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF 3 , OCF 3 . CN, amino, nitro, aryl and a monocyclic 5 to 6-membered heteroaryl group, or a bicyclic heteroaryl group composed of a monocyclic 5 to 6-membered heteroaryl group fused to a benzene ring and which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy, halogen, CF 3 , OCF 3 , CN, amino, nitro, aryl and a monocyclic 5 to 6-membered heteroaryl group. The compounds of the invention are useful as nicotinic ACh receptor ligands.

This application is a Continuation of PCT International Application No.PCT/DK98/00226 filed on May 29, 1998, which designated the UnitedStates, and on which priority is claimed under 35 U.S.C. § 120, theentire contents of which are hereby incorporated by reference.

The present invention relates to novel Azabicyclooctane and heptanederivatives which are cholinergic ligands at nicotinic ACh receptors.The compounds of the invention are useful for the treatment of conditionor disorders or diseases involving the cholinergic system of the centralnervous system, pain, inflammatory diseases, diseases caused by smoothmuscle contractions and as assistance in the cessation of chemicalsubstance abuse.

BACKGROUND

The endogenous cholinergic neurotransmitter, acetylcholine, exert itsbiological effect via two types of cholinergic receptors; the muscarinicACh receptors and the nicotinic ACh receptors. As it is well establishedthat muscarinic ACh receptors dominate quantitatively over nicotinic AChreceptors in the brain area important to memory and cognition, muchresearch aimed at the development of agents for the treatment of memoryrelated disorders have focused on the synthesis of muscarinic AChreceptor modulators. Recently, however, an interest in the developmentof nicotinic ACh receptor modulators has emerged. Several diseases areassociated with degeneration of the cholinergic system i.e. seniledementia of the Alzheimer type, vascular dementia and cognitiveimpairment due to the organic brain damage disease related directly toalcoholism. Indeed several CNS disorders can be attributed to acholinergic deficiency, a dopaminergic deficiency, an adrenergicdeficiency or a serotonergic deficiency. Alzheimer's disease ischaracterised by a profound loss of memory and cognitive functionscaused by a severe depletion of cholinergic neurons, i.e. neurons thatrelease acetylcholine. A reduction in the number of nicotinic AChreceptors are also observed with the progression of Alzheimer's disease.It is believed that the neurons in the cortex that die with theprogression of Alzheimer's disease do so because of lack of stimulationof the nicotinic ACh receptors. It is predicted that treatment ofAlzheimer's patients with nicotinic ACh receptor modulators will notonly improve the memory of patients but in addition act to keep theseneurons alive. Smoking actually seems to protect individuals againstneurodegeneration and compounds behaving on these receptor may verylikely have a generally neuroprotective effect.

However degeneration of the cholinergic system is not limited toindividuals suffering from i.e. Alzheimers disease but is also seen inhealthy aged adults and rats. Therefore it is suggested that thecholinergic system is involved and partly responsible for the memorydisturbances seen in aged animals and humans. Nicotine receptormodulator may therefore be useful in the treatment of Alzheimer'sdisease, memory loss, memory dysfunction, AIDS-dementia, senile dementiaor neurodegenerative disorders.

Parkinsons disease appears to involve degeneration of dopaminergicneurons. One symptom of the disease has been observed to be loss ofnicotinic receptors associated with the dopaminergic neurons andpossibly interfering with the process of release of dopamine. Assustained nicotine administration increases the number of receptorspresent, administration of nicotine receptor modulators may amelioratethe symptoms of Parkinson's disease. Other condition or disorders ordisease ascribed to deficiencies in the dopaminergic system is: drugaddiction, depression, obesity and narcolepsy.

Tourette's syndrome is a neuropsychiatric disorder involving a range ofneurological and behavioral symptoms. It is believed thatneurotransmitter dysfunction is involved though the pathophysiology isstill unknown and that nicotine will be beneficial in the treatment ofthe disease (Devor et. al. The Lancet, vol. 8670 p. 1046,1989).

Schizophrenia is a severe psychiatric illness. Neuroleptic compounds hasbeen used in the treatment of the disease, the effect of the compoundsis believed to be interaction in the dopaminergic system. Nicotine isproposed to be effective in the treatment of schizophrenia (Merriam et.al. Psychiatr. annals, Vol. 23, p. 171-178, 1993 and Adler et. al. Biol.Psychiatry, Vol. 32, p. 607-616,1992.)

Nicotine has been reported to have en effect on neurotransmitter releasein several systems. Release of acetylcholine and dopamine by neuronsupon administration of nicotine has been reported (J. Neurochem. vol.43,1593-1598,1984) and release of norepinephrine by Hall et. al.(Biochem. Pharmacol. vol. 21,1829-1838,1972) Release of serotonin byHery et. al. (Arch. Int. Pharmacodyn. Ther. vol. 296. p. 91-97, 1977).Release of glutamate by Toth et. al (Neurochem. Res. vol. 17, p.265-271,1992).

The serotonin system and dysfunction's of the serotonergic system isbelieved to be involved in diseases or conditions or disorders like:anxiety, depression, eating disorders, obsessive compulsive disorder,panic disorders, chemical substance abuse, alcoholism, pain, memorydeficits and anxiety, pseudodementia, Gansers syndrome, migraine pain,bulimia, obesity, premenstrual syndrome or late luteal phase syndrome,tobacco abuse, post-traumatic syndrome, social phobia, chronic fatiguesyndrome, premature ejaculation, erectile difficulty, anorexia nervosa,disorders of sleep, autism, mutism or trichotillomania.

Nicotine improves concentration and task performance . Thereforecompounds exhibiting nicotine receptor modulating properties will belikely to be useful compounds in the treatment of learning deficit,cognition deficit, attention deficit, attention deficit hyperactivitydisorder and dyslexia.

Tobacco use and especially cigarette smoking is recognised as a serioushealth problem. However nicotine withdrawal symptoms associated withsmoking cessation makes it difficult to break this habit. Withdrawalsymptoms include anger, anxiety, difficulties in concentrating,restlessness, decreased heart rate and increased appetite and weightgain. Nicotine itself has shown to ease the withdrawal symptoms.

Withdrawal from addictive substances, i.e. opiates, benzodiazepines,ethanol, tobacco or nicotine, is in general a traumatic experiencecharacterised by anxiety and frustration. Nicotine has been found to beeffective in reducing anger, irritability, frustration and feelings oftension without causing general response depression, drowsiness orsedation and compounds having same characteristics as nicotine is likelyto have same effects.

Mild to moderate pain is normally treatable with NSAID's (non-steroidalanti-inflammatory drugs) while opiates are used preferentially formoderate to severe pain. The opiates have some well-known side-effects,including chemical dependence and abuse potential as well as adepressive effect on the respiratory and gastrointestinal system. Thereexists therefore a strong need for analgesic compounds that do notexhibit these side effects and which can relieve mild, moderate andsevere pain of acute, chronic or recurrent character as well as migrainepain and postoperative pain, phantom limb pain.

Epibatidine, a compound isolated from the skin of a poison frog, is avery potent analgesic with an approximate potency of 500 times that ofmorphine. The analgesic effect is not affected by naloxone, which is anindication of a negligible affinity for the opiate receptors.Epibatidine is an nicotinic cholinergic receptor agonist and it istherefore very likely, that compounds possessing this receptormodulating character will also show a strong analgesic response. Thecompounds of the present invention has proven useful for modulation ofsmooth muscle. contractions and may therefore be used in the treatmentor prevention of condition or disorders or diseases inherent from smoothmuscle contractions like i.e. convulsive disorders, angina pectoris,premature labor, convulsions, diarrhoea, asthma, epilepsy, tardivedyskinesia, hyperkinesia.

Further, it is well known that nicotine has an effect on appetite and itis predicted that modulators at the nicotine ACh receptor may be usefulas appetite suppressants in the treatment of obesity and eatingdisorders.

The cholinergic receptors play an important role in the functioning ofmuscles, organs and generally in the central nervous system. There arealso complex interactions between cholinergic receptors and the functionof receptors of other neurotransmitters such as dopamine, serotonin andnoradrenaline.

It is likely that nicotine receptor modulator compounds can be effectivein preventing or treating conditions or disorders or diseases like:inflammation, inflammatory skin conditions, Chron's disease,inflammatory bowel disease, ulcerative collitis, diarrhoea,neurodegeneration, perpherical neuropathy, amyotrophic lateralsclerosis, nociception, endocrine disorders, thyrotoxicosis,pheochromocytoma, hypertension, arrhytmias, mania, manic depression,Huntington's disease, jetlag.

The compounds of the present invention are nicotine receptor modulatorsand has the potential to exhibit nicotinic pharmacology, preferentiallywithout the side effects associated with nicotine itself. Additionally,the compounds are expected to have the potential as enhancers ofneurotransmitter secretion and suppress symptoms associated with a lowactivity of neurotransmitters.

Close structural analogues to the compounds of the present invention hasbeen described in prior art:

J. Org. Chem. (1995), 60(16), 4969-4961 describes a synthesis of aminesby Schmidt reaction of aliphatic azides whereby1-butylhexahydro-2-phenyl-1H-azepine is produced. Monatsh. Chem. (1971),102(2), 513-516 describes synthetic methods for achieving3,4,5,6-tetrahydro-7-phenyl-2H-azepine,7-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-Azepine,hexahydro-2-phenyl-1H-azepine, and2-(3,4-dimethoxyphenyl)hexahydro-1H-azepine; Tetrahedron Lett. (1978).(22),1 901-1904 describes the iodomethylation and stereoselectivity ofnicotine and related compounds such ashexahydro-1-methyl-2-(S)(3-pyridinyl)-1H-azepine. J. Am. Chem. Soc.(1989), 111(16), 6465-6 products formed by a photochemical reaction,such product being for example: hexahydro-1 -methyl-2-phenyl-1H-azepineand octahydro-1-methyl-2-phenyl-azocine;

J. Chromotogr., Biomed. Appl. (1993), 619(1), 49-61 describes achromatographic-mass spectrometric method for determination of anabasineand other tobacco alkaloids such as:hexahydro-2-(3-pyridinyl)-1H-azepine and3,4,5,6-tetrahydro-7-(3-pyridinyl)-2H-azepine; The compound1-H-2-(3-pyridyl)azacycloheptane was previously described in TetrahedronLetters (1978), 22, 1909-1904;

OBJECTS OF THE INVENTION

It is an object of the present invention to provide novelAzabicyclooctane and heptane derivatives which are useful for thetreatment of a range of diseases and disorders characterised bydecreased cholinergic function or responsive to the activity ofnicotinic ACh receptor modulators.

Another object of the present invention is to provide novelpharmaceutical compositions containing these compounds, as well asmethods for the preparation thereof and methods for the treatmenttherewith.

Other objects will become apparent hereinafter to one skilled in theart.

THE PRESENT INVENTION

In the context of this invention “treating” covers treatment,prophylaxis, or alleviation and “disease” covers a disease or a disorderor a condition.

In In the context of this invention “modulator” covers agonists, partialagonists, antagonists and allosterical modulators, the context of thisinvention disorders in the central nervous system covers for example:neurodegenerative disorders, cognitive or memory dysfunction,Alzheimer's disease, Parkinson's disease, Huntington's disease,Amyotrophic Lateral Sclerosis, Gilles de la Tourettes syndrome,attention deficit hyperactivity disorder, anxiety, depression, mania,manic depression, schizophrenia, obsessive compulsive disorders, eatingdisorders like anorexia nervosa, bulimia and obesity, narcolepsy,nociception, memory loss, memory dysfunction, AIDS-dementia, seniledementia, peripherial neuropathy, learning deficit, cognition deficit,attention deficit, autism, dyslexia, tardive dyskinesia, hyperkinesia,epilepsy, bulimia, post-traumatic syndrome, social phobia, chronicfatigue syndrome, disorders of sleep, pseudodementia, Ganser's syndrome,prementraul syndrome, late luteal phase syndrome, chronic fatiguesyndrome, premature ejaculation, erectile difficulty, mutism andtrichotillomania.

In the context of this invention inflammatory conditions covers forexample: inflammatory skin conditions like acne and rosacea, Chron'sdisease, inflammatory bowel disease, ulcerative collitis, diarrhoea.

Diseases associated with smooth muscle contractions covers for example:convulsive disorders, angina pectoris, premature labor, convulsions,diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia.

In the context of this invention pain covers for example chronic, acuteand recurrent pain, postoperative pain, migraine pain or phantom limbpain;

Abuse of chemical substances covers smoking as well as use of othernicotine containing products, use of opiods like heroin, cocaine andmorphine, use of benzodiazepines or alcohol. In this context “treatment”covers treatment, prevention, profylaxis and alleviation of withdrawalsymptoms and abstinence as well as treatment resulting in a voluntarydiminished intake of the addictive substance.

The invention then, inter alia, comprises the following, alone or incombination:

A compound having the formula,

any of its enantiomers or any mixture thereof, or a pharmaceuticallyacceptable salt thereof;

wherein

n is 0, or 1;

R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl or aralkyl; and

R¹ is

aryl which may be substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, alkoxy, cycloalkoxy, thioalkoxy, thiocycloalkoxy,methylenedioxy, aryloxy, halogen, CF₃, OCF₃, CN, amino, nitro, aryl anda monocyclic 5 to 6-membered heteroaryl group; or

a monocyclic 5 to 6membered heteroaryl group which may be substitutedone or more times with substituents selected from the group consistingof alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy,cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy,halogen, CF₃, OCF3, CN, amino, nitro, aryl and a monocyclic 5 to6-membered heteroaryl group; or

a bicyclic heteroaryl group composed of a monocyclic 5 to 6 memberedheteroaryl group fused to a benzene ring and which may be substitutedone or more times with substituents selected from the group consistingof alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy,cycloalkoxy, thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy,halogen, CF₃, OCF₃, CN, amino, nitro, aryl and a monocyclic 5 to 6membered heteroaryl group.

A preferred embodiment of the invention is a compound of formulas 1 and2 wherein

n is 0, or 1;

R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl or aralkyl; and

R¹ is

aryl which is substituted one or more times with substituents selectedfrom the group consisting of cycloalkyl, cycloalkylalkyl alkenyl,alkynyl, thioalkoxy, cycloalkoxy, thiocycloalkoxy, methylenedioxy,aryloxy, halogen, CF₃, OCF₃, CN, amino, nitro, aryl and a monocyclic 5to 6-membered heteroaryl group; or

a monocyclic 5 to 6-membered heteroaryl group which may be substitutedone or more times with substituents selected from the group consistingof alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy,thioalkoxy, thiocycloalkoxy, methylenedioxy, aryloxy cycloalkoxy,halogen, CF₃, OCF₃, CN, amino, nitro, aryl and a monocyclic 5 to6-membered heteroaryl group; or

a bicyclic heteroaryl group composed of a monocyclic 5 to 6 memberedheteroaryl group fused to a benzene ring and which may be substitutedone or more times with substituents selected from the group consistingof alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy,thioalkoxy, thiocycloalkoxy cycloalkoxy, methylenedioxy, aryloxy,halogen, CF₃, OCF₃, CN, amino, nitro, aryl and a monocyclic 5 to 6membered heteroaryl group; provided that the compound is not:hexahydro-2-(3-pyridinyl)-1H-azepine or hexahydro-1-methyl-2-(S)-(3-pyridinyl)-1H-azepine.

Another preferred embodiment of the invention is compound formula 1 or2, wherein

n is 0, or 1;

R is hydrogen or methyl and

R¹ is 3-pyridyl, 3-quinolinyl, 6-thioethyl-3-pyridyl or5-thioethyl-3-pyridyl.

Another preferred embodiment of the invention is a compound as abovewhich is

(R,S)-1-H-2-(3-pyridyl)azacyclooctane;

(R,S)-1-H-2-(3-pyridyl)azacycloheptane;

(R,S)-1-H-2-(3-quinolinyl)azacyclooctane;

(R,S)-1-H-2-(6-thioethyl-3-pyridyl)azacycloheptane;

(R,S)-1-H-2[5-thioethyl-3-pyridyl)azacycloheptane;

(R,S)-1-H-2-(5-thioethyl-3-pyridyl)azacyclooctane;

(R,S)-1-Methyl-2-(3-pyridyl)azacyclooctane;

(R,S)-1-Methyl-2-(3-quinolinyl)azacyclooctane;

(R,S)-1-Methyl-2-(6-thioethyl-3-pyridyl)azacycloheptane;

(R,S)-1-Methyl-2-(5-thioethyl-3-pyridyl)azacycloheptane;

(R,S)-1-Methyl-2-(5-thioethyl-3-pyridyl)azacyclooctane;

1c:2-(3Pyridyl)azacyclooct-1-ene;

2-(3-Quinolinyl)azacyclooct-1-ene or

2-(5-thioethyl-3-pyridyl)azacyclooct-1-ene; or a pharmaceuticallyacceptable addition salt thereof.

a pharmaceutical composition, comprising a therapeutically effectiveamount of a compound as above, or a pharmaceutically acceptable additionsalt thereof, together with at least one pharmaceutically acceptablecarrier or diluent;

the use of a compound as above for the manufacture of a medicament forthe treatment or prevention of a condition or disorder or disease of aliving animal body, including a human, which condition or disorder ordisease is responsive to the activity of nicotinic ACh receptormodulators;

the use of a compound as above wherein the disease to be treated ispain, a disease in the central nervous system, a disease caused bysmooth muscle contraction, neurodegeneration, inflammation, chemicalsubstance abuse or withdrawal symptoms caused by the cessation of intakeof the chemical substance.

The use as above wherein the disease is a disease in the central nervoussystem said disease being Alzheimers disease, Parkinson's disease,memory dysfunction or attention deficit hyperactivity disorder.

The use as above wherein the disease to be treated is chemical substanceabuse or withdrawal symptoms caused by the cessation of intake of thechemical substance, said chemical substance abuse being smoking or useof other nicotine containing products and withdrawal symptoms caused bycessation of use of nicotine containing products;

a method for the preparation of the compounds as above comprising thestep of

a) reacting a compound having the formula

 wherein n is as defined above, with a compound of the formula R¹-Li,wherein R¹ is as defined above; to form a compound of formula

 wherein n and R¹ is as defined above, or

b) oxidising a compound having the formula

 wherein R¹ and n is as defined above, to form a compound having theformula

 wherein R¹ and n is as defined above;

a method of treating a disease of a living animal body, including ahuman, which disease is responsive to the activity of nicotinic AChreceptor modulators, comprising the step of administering to such aliving animal body, including a human, in need thereof a therapeuticallyeffective amount of a compound as above;

the method as above wherein pain, a disease of the central nervoussystem, neurodegeneration, inflammation, chemical substance abuse,withdrawal symptoms from cessation of use of addictive substances, or adisease caused by smooth muscle contractions is treated.

The method as above wherein chemical substance abuse or withdrawalsymptoms caused by the cessation of intake of the chemical substance,said chemical substance abuse being smoking or use of other nicotinecontaining products and withdrawal symptoms caused by cessation of useof nicotine containing products, is treated.

The method as above wherein a disease in the central nervous system,said disease being Alzheimer's disease, Parkinson's disease, memorydysfunction or attention deficit hyperactivity disorder, is treated.

Examples of pharmaceutically acceptable addition salts include inorganicand organic acid addition salts such as the hydrochloride, hydrobromide,phosphate, nitrate, perchlorate, sulphate, citrate, lactate, tartrate,maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate,benzenesulfonate, methanesulfonate, stearate, succinate, glutamate,glycollate, toluene-p-sulphonate, formate, malonate,naphthalene-2-sulphonate, salicylate and the acetate. Such salts areformed by procedures well known in the art.

Other acids such as oxalic acid, while not in themselvespharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining compounds of the invention andtheir pharmaceutically acceptable acid addition salts.

Halogen is fluorine, chlorine, bromine or iodine.

Alkyl means a straight chain or branched chain of one to six carbonatoms, including but not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, and hexyl; methyl, ethyl, propyl andisopropyl are preferred groups.

Cycloalkyl means cyclic alkyl of three to seven carbon atoms, includingbut not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Alkenyl means a group of from two to six carbon atoms, including atleast one double bond, for example, but not limited to ethenyl, 1,2- or2,3-propenyl, 1,2-, 2,3-, or 3,4-butenyl.

Alkynyl means a group of from two to six carbon atoms, including atleast one triple bond, for example, but not limited to ethynyl, 1,2- or2,3-propynyl, 1,2- or 2,3- or 3,4-butynyl.

Cycloalkylalkyl means cycloalkyl as above and alkyl as above, meaningfor example, cyclopropylmethyl.

Alkoxy is O-alkyl, wherein alkyl is as defined above.

Cycloalkoxy is O-cycloalkyl, wherein cycloalkyl is as defined above.

Thioalkoxy is S-alkyl, wherein alkyl is as defined above.

Thiocycloalkoxy is S-cycloalkyl wherein cycloalkyl is as defined above.

Amino is NH₂ or NH-alkyl or N-(alkyl)₂, wherein alkyl is as definedabove.

A monocyclic 5- to 6-membered heteroaryl group contain one, two three orfour heteroatoms and includes, for example, oxazol-2-yl, oxazol-4-yl,oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl,1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl,1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1 -pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl and1-pyrazolyl, 3-pyrazolyl, and 4-pyrazolyl.

A bicyclic heteroal group composed of a 5 to 6 membered monocyclicheteroaryl group and a fused benzene ring means a monocyclic 5 to 6membere d heteroaryl group as above which is fused to a benzene ringincluding, for example, 2-, 3-, 4-, 5-, 6-, 7-benzofuranyl, 1-, 2-, 4-,5- benzimidazolyl, 2-, 3-, 4-, 5-, 6-, 7- 8-quinolinyl and 1l-, 3-, 4-,5-, 6-, 7-, 8-isoquinolinyl.

Aryl is an aromatic hydrocarbon; such as phenyl and naphthyl.

Aryloxy is O-aryl, wherein aryl is as defined above.

Further, the compounds of this invention may exist in unsolvated as wellas in solvated forms with pharmaceutically acceptable solvents such aswater, ethanol and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thisinvention.

It will be appreciated by those skilled in the art that the compounds ofthe present invention contain several chiral centres and that suchcompounds exist in the form of isomers (i.e. enantiomers). The inventionincludes all such isomers and any mixtures thereof including racemicmixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods, for example, by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptically active matrix. Racemic compounds of the present invention canthus be resolved into their optical antipodes, e.g., by fractionalcrystallization of d- or l- (tartrates, mandelates, orcamphorsulphonate) salts for example. The compounds of the presentinvention may also be resolved by the formation of diastereomeric amidesby reaction of the compounds of the present invention with an opticallyactive activated carboxylic acid such as that derived from (+) or (−)phenylalanine, (+) or (−) phenylglycine, (+) or (−) camphanic acid or bythe formation of diastereomeric carbamates by reaction of the compoundsof the present invention with an optically active chioroformate or thelike.

Additional methods for the resolvation of optical isomers, known tothose skilled in the art may be used, and will be apparent to theaverage worker skilled in the art. Such methods include those discussedby J. Jaques, A. Collet, and S. Wilen in “Enantiomers, Racemates, andResolutions”, John Wiley and Sons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials.

The compounds of the invention may be prepared by any conventionalmethod useful for the preparation of analogous compounds and asdescribed in the examples below.

Starting materials for the processes described in the present patentapplication are known or can be prepared by known processes fromcommercially available materials.

A compound of the invention can be converted to another compound of theinvention using conventional methods.

The products of the reactions described herein are isolated byconventional means such as extraction, crystallisation, distillation,chromatography, and the like.

Biology

Nicotinic ACh receptors in the brain are pentameric structures composedof subunits distinct from those found in skeletal muscles. The existenceof eight α-subunits (α2-α9) and three β-subunits (β2-β4) in themammalian brain has been described.

The predominant subtype with high affinity for nicotine is comprised ofthree α₄ and two β₂ subunits.

The affinity of compounds of the invention for nicotinic ACh receptorshave been investigated in three test for in vitro inhibition of³H-epibatidin binding, ³H-α-bunga-rotoxin binding and ³H-cytisinebinding as described below:

In vitro inhibition of ³H-cytisine binding

The predominant subtype with high affinity for nicotine is comprised ofα₄ and β₂ subunits. nAChRs of the latter type can selectively belabelled by the nicotine agonist ³H-cytisine.

Tissue Preparation

Preparations are performed at 0-4° C. unless otherwise indicated.Cerebral corticies from male Wistar rats (150-250 g) are homogenized for20 sec in 15 ml Tris, HCl (50 mM, pH 7.4) containing 120 mM NaCl, 5 mMKCl, 1 mM MgCl₂ and 2.5 mM CaCl₂ using an Ultra-Turrax homogenizer. Thehomogenate is centrifuged at 27,000×g for 10 min. The supernatant isdiscarded and the pellet is resuspended in fresh buffer and centrifugeda second time. The final pellet is resuspended in fresh buffer (35 mlper g of original tissue) and used for binding assays.

Assay

Aliquots of 500 μl homogenate are added to 25 μl of test solution and 25μl of ³H-cytisine (1 nM, final concentration), mixed and incubated for90 min at 2° C. Non-specific binding is determined using (−)-nicotne(100 μM, final concentration). After incubation the samples are added 5ml of ice-cold buffer and poured directly onto Whatman GF/C glass fibrefilters under suction and immediately washed with 2×5 ml ice-coldbuffer. The amount of radioactivity on the filters is determined byconventional liquid scintillation counting. Specific binding is totalbinding minus non-specific binding.

In vitro inhibition of ³H-α-bungarotoxin binding Rat brain

α-Bungarotoxin is a peptide isolated from the venom of the Elapidaesnake Bungaurs multicinctus (Mebs et al., Biochem. Biophys. Res.Commun., 44(3), 711 (1971)) and has high affinity for neuronal andneuromuscular nicotinic receptors, where it acts as a potent antagonist.³H-α-Bungarotoxin binds to a single site in rat brain with an uniquedistribution pattern in rat brain (Clarke et al., J. Neurosci. 5,1307-1315 (1985)).

³H-α-Bungarotoxin labels nAChR formed by the α₇ subunit isoform found inbrain and the α₁ isoform in the neuromuscular junction (Changeaux, FidiaRes. Found. Neurosci. Found. Lect. 4, 21-168 (1990). Functionally, theα₇ homo-oligomer expressed in oocytes has a calcium permeability greaterthan neuromuscular receptors and, in some instances greater than NMDAchannels (Seguela et al., J. Neurosci. 13, 596-604 (1993).

Tissue preparation

Preparations are performed at 0-4° C. unless otherwise indicated.Cerebral cortices from male Wistar rats (150-250 g) are homogenized for10 sec in 15 ml 20 mM Hepes buffer containing 118 mM NaCl, 4.8 mM KCl,1.2 mM MgSO₄ and 2.5 mM CaCl₂ (pH 7.5) using an Ultra-Turraxhomogenizer. The tissue suspension is centrifuged at 27,000×g for 10min. The supernatant is discarded and the pellet is washed twice bycentrifugation at 27,000×g for 10 min in 20 ml fresh buffer, and thefinal pellet is resuspended in fresh buffer containing 0.01% BSA (35 mlper 9 of original tissue) and used for binding assays.

Assay

Aliquots of 500 μl homogenate are added to 25 μl of test solution and 25μl of ³H-α-bungarotoxin (2 nM, final concentration), mixed and incubatedfor 2 h at 370C. Non-specific binding is determined using (−)-nicotine(1 mM, final concentration). After incubation the samples are added 5 mlof ice-cold Hepes buffer containing 0.05% PEI and poured directly ontoWhatman GF/C glass fibre filters (presoaked in 0.1% PEI for at least 6h) under suction and immediately washed with 2×5 ml ice-cold buffer. Theamount of radioactivity on the filters is determined by conventionalliquid scintillation counting. Specific binding is total binding minusnon-specific binding.

In vitro inhibition of ³H-epibatidin binding

Epibatidin is an alkaloid that was first isolated from the skin of theEcuadoran frog Epipedobates tricolor and was found to have very highaffinity for neuronal nicotinic receptors, where it acts as a potentagonist. ³H-epibatidin binds to two sites in rat brain, both of whichhave pharmacological profiles consistent with neuronal nicotinicreceptors and a similar brain regional distribution (Hougling et al.,Mol. Pharmacol. 48, 280-287 (1995)).

The high affinity binding site for ³H-epibatidin is most certainlybinding to the α₄β₂ subtype of nicotinic receptors. The identity of thelow affinity site is still unknown; does it represent a second nicotinicreceptor or a second site in the same receptor. The inability ofa-bungarotoxin to compete for ³H-epibatidin binding sites indicates thatneither site measured represents the nicotinic receptor composed of α₇subunits.

Tissue preparation

Preparations are performed at 0-4° C. unless otherwise indicated. Theforebrain (÷cerebellum) from a male Wistar rat (150-250 g) ishomogenized for 10-20 sec in 20 ml Tris, HCl (50 mM, pH 7.4) using anUltra-Turrax homogenizer. The tissue suspension is centrifuged at27,000×g for 10 min. The supernatant is discarded and the pellet iswashed three times by centrifugation at 27,000×g for 10 min in 20 mlfresh buffer, and the final pellet is resuspended in fresh buffer (400ml per g of original tissue) and used for binding assays.

Assay

Aliquots of 2.0 ml homogenate are added to 0.100 ml of test solution and0.100 ml of ³H-epibatidin (0.3 nM, final concentration), mixed andincubated for 60 min at room temperature. Non-specific binding isdetermined using (−)-nicotine (30 μM, final concentration). Afterincubation the samples are poured directly onto Whatman GF/C glass fibrefilters (presoaked in 0.1 % PEI for at least 20 min) under suction andimmediately washed with 2×5 ml ice-cold buffer. The amount ofradioactivity on the filters is determined by conventional liquidscintillation counting. Specific binding is total binding minus,non-specific binding.

Results are given as IC₅₀ values; the concentration (μM) that inhibitbinding of the radioactive ligand by 50 %.

Below test results for compounds of the invention are presented:(Compound numbers refers to the examples)

) ³H-α- ³H-cytisine ³H-epibatidin bungarotoxin Compound IC₅₀ (μM) IC₅₀(μM) IC₅₀ (μM) 1a 0.2000 0.5500 2.000 3a 1.300 7.500 >30.000 5a 4.3004.800 >30.000 6a 1.0 — — 1b 0.5600 1.500 67.00 5b 1.9500 — — 1c 0.05900.2500 1.400

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of thechemical compound of the invention.

While a chemical compound of the invention for use in therapy may beadministered in the form of the raw chemical compound, it is preferredto introduce the active ingredient, optionally in the form of aphysiologically acceptable salt, in a pharmaceutical compositiontogether with one or more adjuvants, excipients, carriers and/ordiluents.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the chemical compound of the invention, or apharmaceutically acceptable salt or derivative thereof, together withone or more pharmaceutically acceptable carriers therefor and,optionally, other therapeutic and/or prophylactic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof.

Pharmaceutical compositions of the invention may be those suitable fororal, rectal, nasal, topical (including buccal and sub-lingual),transdermal, vaginal or parenteral (including intramuscular,sub-cutaneous and intravenous) administration, or those in a formsuitable for administration by inhalation or insufflation.

The chemical compound of the invention, together with a conventionaladjuvant, carrier, or diluent, may thus be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed, as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, in the form of suppositories forrectal administration; or in the form of sterile injectable solutionsfor parenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

The chemical compound of the present invention can be administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a chemical compound of the invention ora pharmaceutically acceptable salt of a chemical compound of theinvention.

For preparing pharmaceutical compositions from a chemical compound ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersible.granules. A solid carrier can be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The chemical compound according to the present invention may thus beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilisers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the chemical compoundaccording to the invention may be formulated as ointments, creams orlotions, or as a transdermal patch. Ointments and creams may, forexample, be formulated with an aqueous or oily base with the addition ofsuitable thickening and/or gelling agents. Lotions may be formulatedwith an aqueous or oily base and will in general also contain one ormore emulsifying agents, stabilising agents, dispersing agents,suspending agents, thickening agents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

The dose administered must of course be carefully adjusted to the age,weight and condition of the individual being treated, as well as theroute of administration, dosage form and regimen, and the resultdesired. It is presently contemplated that compositions containing offrom about 0.1 to about 500 mg of active ingredient per unit dosage,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

A satisfactory result can, in certain instances, be obtained at a dosageas low as 0.005 mg/kg i.v. and 0.01 mg/kg p.o. The upper limit of thedosage range is about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred rangesare from about 0.001 to about 1 mg/kg i.v. and from about 0.1 to about10 mg/kg p.o.

Method of Treating

The compounds of the present invention are valuable nicotinic AChreceptor modulators and therefore useful for the treatment of a range ofailments involving cholinergic dysfunction as well as a range ofdisorders responsive to the activity of nicotinic ACh receptormodulators. The compounds may be used in the treatment, prevention,profylaxis or alleviation of a disease, disorder or condition of thecentral nervous system as for example: neurodegenerative disorders,cognitive or memory dysfunction, Alzheimer's disease, Parkinson'sdisease, Huntington's disease, Amyotrophic Lateral Sclerosis, Gilles dela Tourettes syndrome, attention deficit hyperactivity disorder,anxiety, depression, mania, manic depression, schizophrenia, obsessivecompulsive disorders, eating disorders like anorexia nervosa, bulimiaand obesity, narcolepsy, nociception, memory loss, memory dysfunction,AIDS-dementia, senile dementia, peripherial neuropathy, learningdeficit, cognition deficit, attention deficit, autism, dyslexia, tardivedyskinesia, hyperkinesia, epilepsy, bulimia, post-traumatic syndrome,social phobia, chronic fatigue syndrome, disorders of sleep,pseudodementia, Gansers syndrome, prementraul syndrome, late lutealphase syndrome, chronic fatigue syndrome, premature ejaculation,erectile difficulty, mutism and trichotillomania.

The compounds of this invention may also be used in the treatment ofinflammatory conditions as for example: inflammatory skin conditionslike acne and rosacea, Chron's disease, inflammatory bowel disease,ulcerative collitis, diarrhoea.

Also the compounds of the invention may be used in the treatment ofdiseases associated with smooth muscle contractions as for example:convulsive disorders, angina pectoris, premature labor, convulsions,diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia.

The compounds of this invention may also be used in the treatment ofpain as for example chronic, acute and recurrent pain, postoperativepain, migraine pain or phantom limb pain;

The compounds of the present invention may also be used for theassistance in cessation of abuse of chemical substances as for examplesmoking cessation as well as cessation of use of other nicotinecontaining products, cessation of use of opiods like heroin, cocaine andmorphine and cessation of use of benzodiazepines or alcohol. In thecontext of the present invention “treatment” means as well treatment asprevention, profylaxis and alleviation of withdrawal symptoms andabstinence as well as treatment resulting in a voluntary diminishedintake of the addictive substance.

Suitable dosage range are 0.1-500 milligrams daily, and especially 10-70milligrams daily, administered once or twice a day, dependent as usualupon the exact mode of administration, form in which administered, theindication toward which the administration is directed, the subjectinvolved and the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

I.p. means intraperetoneally, which is a well known route ofadministration. P.o. means peroral, which is a well known route ofadministration.

The following examples will illustrate the invention further, however,they are not to be construed as limiting.

EXAMPLES

General

All reactions involving air sensitive reagents or intermediates wereperformed under nitrogen and in anhydrous solvents. Magnesium sulfatewas used as drying agent in the workup-procedures and solvents wereevaporated under reduced pressure.

1-Aza-1-chlorooctane

To an aqueous solution of sodium hypochlorite (4 %, 500 ml) was added toazacyclooctane (20.0 g, 177 mmol) dropwise at 10° C. The mixture wasstirred for 5 min at 10° C., followed by extraction four times withethyl ether (60 ml). The crude product was purified by destination34-36° C., 1 mm Hg. Yield 17.2 g, 69 %.

1-Aza-oct-1-en

A mixture of 1-aza-1-chloroctane (17.2 g, 121 mmol), potassiumsuperoxide (19.0 g, 267 mmol), 18-crown-6-ether (0.25 g , 0.95 mmol) wasstirred at room temperature over night.

3-Bromo-5-thioethoxypyridine

A mixture of sodium thioethoxide (5.86 g, 69.6 mmol),3.5-Dibromopyridine (15.0 g, 63.3 mmol) and dimethyl sulfoxide (75 ml).The mixture was stirred at 90° C. for 2 h. Sodium hydroxide (300 ml, 1M) was added and the mixture was extracted twice with diethyl ether (100ml). Chromatography on silica gel with dichloromethane eluent gave thetitle compound as an oil. Yield 8.55 g, 58 %.

3-Bromo-6-thioethoxypyridine

A mixture of sodium thioethoxide (7.81 g, 92.9 mmol),2.5-Dibromopyridine (20.0 g, 84.4 mmol) and dimethyl sulfoxide (100 ml).The mixture was stirred at 20° C. overnight. Sodium hydroxide (300 ml, 1M) was added and the mixture was extracted twice with diethyl ether (200ml). Chromatography on silica gel with dichloromethane: petroleum ether,1:2 as eluent, gave the title compound as an oil. Yield 16.8 g, 85 %.

Method A

1a: (R,S)-1-H-2-(3-pyridyl)azacyclooctane fumaric acid salt

Tert-butyllithium (142.8 ml, 242.8 mmol) was added to 3-Bromopyridine(19.2 g, 121.4 mmol) in anhydrous diethyl ether at −85-(−95)° C. Themixture was stirred for 0.5 h at −95° C. A crude mixture of1-aza-oct-1-en was filtered under inert atmosphere followed by anhydrousdiethyl ether, and the filtrate was added to the reaction mixture at−90-(−95)° C. The mixture was stirred for 0.5 h at −90° C. Thetemperature was allowed to reach −40° C. and water (15 ml) was addedslowly. The reaction mixture was allowed to reach room temperature andstir for 15 h. Sodium hydroxide (200 ml, 0.5 M) was added and the phaseswere separated. The water phase was extracted three times with diethylether. The collected organic phases were purified by chromatography onsilica gel with dichloromethane and ethanol (9:1) as solvent. Yield 12.6g, 54 %. The corresponding salt was obtained by addition of a diethylether and methanol mixture (9:1) saturated with fumaric acid. Mp141-142° C.

2a: (R,S)-1-H-2-(3-pyridyl)azacycloheptane fumaric acid salt

Prepared according to method A. Mp 130-131° C. Known in the literatureTetrahedron Lett., 1901 (1978).

3a: (R,S)-1-H-2-(3-quinolinyl)azacyclooctane fumaric acid salt

Prepared according to method A. Mp 172-174° C. 4a:(R,S)-1-H-2-(6thioethyl-3-pyridyl)azacycloheptane fumaric acid salt

Prepared according to method A. Mp 140-142° C.

5a:(R,S)-1-H-2-(5-thioethyl-3-pyridyl)azacycloheptane fumaric acid salt

Prepared according to method A. Mp 159-161° C.

6a:(R,S)-1-H-2-(5-thioethyl-3-pyridyl)azacyclooctane

Prepared according to method A. Isolated as an oil.

Method B

1b:(R,S)-1-Methyl-2-(3-pyridyl)azacyclooctane

A mixture of (R,S)-1-H-2-(3-pyridyl)azacyclooctane (4.0 g, 21.0 mmol),formaldehyde (6.3 g, 37 %) and formic acid (10.6 g, 88 %) was refluxedfor 16 h. The mixture was evaporated to dryness and sodium hydroxide (50ml) was added followed by extraction twice with ethyl acetate (30 ml).The product was isolated as an oil. Yield 4.0 g, 93 %.

2b:(R,S)-1-Methyl-2(3-quinolinyl)azacyclooctane

Prepared according to method B. Isolated as an oil

3b: (R,S)-1-Methyl-2-(6thioethyl-3-pyridyl)azacycloheptane

Prepared according to method B. Isolated as an oil.

4b: (R,S)1-Methyl-²-(5-thioethyl-3-pyridyl)azacycloheptane

Prepared according to method B. Isolated as an oil.

5b:(R,S)-1-Methyl-2-(5-thioethyl-3-pyridyl)azacyclooctane fumaric acidsalt

Prepared according to method B. Mp 143.5-145.5° C.

Method C

1c: 2-(3-Pyridyl)azacyclooct-1-ene

(R,S)-1-H-2-(3-pyridyl)azacycloctane (2.0 g, 10.5 mmol) was addeddropwise to an aqueous solution of sodium hypochlodte (90 ml, 47.3 mmol)at 10° C. and stirred for 5 min. The mixture was extracted three timeswith dichloromethane (30 ml). The crude product, dried overnight undervacuum and sodium hydroxide: (R,S)-1-chloro-2-(3-pyridyl)-azacyclooctane(2.1 g, 9.3 mmol) was mixed with potassium superoxide (1.46 g, 20.6mmol) and 18- crown-6-ether (0.30 g, 1.1 mmol) in tetrahydrofuran andstirred at room temperature for two days. Aqueous sodium hydroxide (100ml, 1 M) was added, the mixture was extracted twice with ethyl acetate(40 ml) The crude product was purified by chromatography on silica gelwith dichloromethane and ethanol and concentrated ammonia (89:9:1) assolvent. The title compound was isolated as an oil, yield 0.40 g, 23 %.

2c: ²-(³-Quinolinyl)azacyclooct-1-ene fumaric acid salt

Prepared according to method C. Mp 169-171° C.

3c: 2-(5-thioethyl-3-pyridyl)azacyclooct-1-ene

Prepared according to method C.

What is claimed is:
 1. An azacyclooctane compound of one of theformulae,

enantiomers and mixtures of enantiomers thereof, and pharmaceuticallyacceptable salts thereof, wherein R is hydrogen or alkyl, and R¹ is: apyridyl group which may be substituted with one or more substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, alkynyl, alkoxy, thioalkyl, cycloalkoxy,thiocycloalkyl, methylenedioxy, aryloxy, halogen, CF₃, OCF₃, CN, amino,nitro, aryl, and a monocyclic 5-to 6-membered heteroaryl group; or aquinolinyl group which may be substituted with one or more substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, alkynyl, alkoxy, thioalkyl, cycloalkoxy,thiocycloalkyl, methylenedioxy, aryloxy, halogen, CF₃, OCF₃, CN, amino,nitro, aryl, and a monocyclic 5-to 6-membered heteroaryl group.
 2. Theazacyclooc tane compound of claim 1, wherein R is hydrogen or methyl andR¹ is 3-pyridyl, 3-quinolinyl, 6-thioethyl-3-pyridyl, or5-thioethyl-3-pyridyl.
 3. The azacyclooctane compound of claim 1, whichis (R,S)-1-H-2-(3-pyridyl)azacyclooctane, or a pharmaceuticallyacceptable addition salt thereof.
 4. The azacyclooctane compound ofclaim 1, which is (R,S)-1-H-2-(3-quinolinyl)azacyclooctane, or apharmaceutically acceptable addition salt thereof.
 5. The azacyclooctanecompound of claim 1, which is(R,S)-1-H-2-(5-thioethyl-3-pyridyl)azacyclooctane, or a pharmaceuticallyacceptable addition salt thereof.
 6. The azacyclooctane compound ofclaim 1, which is (R,S)-1-methyl-2-(3-quinolinyl)azacyclooctane, or apharmaceutically acceptable addition salt thereof.
 7. The azacyclooctanecompound of claim 1, which is(R,S)-1-methyl-2-(5-thioethyl-3-pyridyl)azacyclooctane, or apharmaceutically acceptable addition salt thereof.
 8. The azacyclooctanecompound of claim 1, which is 2-(3-pyridyl)azacyclooct-1-ene,or apharmaceutically acceptable addition salt thereof.
 9. The azacyclooctanecompound of claim 1, which is 2-(3-quinolinyl)azacyclooct-1-ene, or apharmaceutically acceptable addition salt thereof.
 10. Theazacyclooctane compound of claim 1, which is2-(5-thioethyl-3-pyridyl)azacyclooct-1-ene, or a pharmaceuticallyacceptable addition salt thereof.
 11. A method for the preparation of acompound according to claim 1 comprising the step of a) reacting acompound having the formula

 wherein n is 1 with a compound of the formula R¹-Li wherein R¹ is apyridyl group which may be substituted with one or more substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, alkynyl, alkoxy, thioalkyl, cycloalkoxy,thiocycloalkyl, methylenedioxy, aryloxy, halogen, CF₃, OCF₃, CN, amino,nitro, aryl, and a monocyclic 5-to 6-membered heteroaryl group; or aquinolinyl group which may be substituted with one or more substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, alkynyl, alkoxy, thioalkyl, cycloalkoxy,thiocycloalkyl, methylenedioxy, aryloxy, halogen, CF₃, OCF₃, CN, amino,nitro, aryl, and a monocyclic 5- to 6-membered heteroaryl group, to forma compound of the formula

 wherein n and R¹ are as defined above, or b) oxidizing a compoundhaving the formula

 wherein n and R¹ are as defined above to form a compound having theformula

wherein n and R¹ are as defined above.
 12. A pharmaceutical composition,comprising a therapeutically effective amount of an azacyclooctanecompound of claim 1, or a pharmaceutically acceptable addition saltthereof, together with at least one pharmaceutically acceptableadjuvant, excipient, carrier, or diluent.
 13. A method of treating adisease of a living animal body, including a human, which disease isresponsive to the activity of nicotinic ACh receptor modulators and isselected from the group consisting of pain, smooth muscle contraction,neurodegeneration, inflammation, AD, PD, learning deficit, cognitiondeficit, attention deficit, AIDS-dementia, senile dementia, attentiondeficit hyperactivity disorder, Tourette's Syndrome, schizophrenia,Amyotrophic Lateral Sclerosis, and depression, or withdrawal symptomscaused by the cessation of intake of a chemical substance, comprisingthe step of administering to such a living animal body, including ahuman, in need thereof, a therapeutically effective amount of anazacyclooctane compound according to claim
 1. 14. The method accordingto claim 13, wherein the withdrawal symptoms are caused by smokingcessation.